1.1 Field of the Invention
The present invention relates generally to the fields of molecular biology and genetics. More particularly, it concerns novel chimeric transcriptional regulatory elements that improve the transcriptional activity of naturally occurring transcriptional regulatory elements, and methods for their use in gene therapy and in particular, prostate-targeted gene expression.
1.2 Description of the Related Art
The prostate specific antigen (PSA) enhancer and promoter can confer exquisite prostate-specific expression of linked reporter gene, with strong androgen stimulation in in vitro transfection of PSA producing prostate cells. Detailed genetic and biochemical analysis of the PSA enhancer core region, −4326 to −3935 with respect to transcriptional start site at +1, clearly established the functional importance of AR binding in this region. Moreover, the cooperative and synergistic binding of AR to the multiple AREs contribute greatly to the androgen responsive transcriptional activity of the PSA enhancer region.
However, when inserted into viral vectors capable of efficient in vivo gene delivery, the native PSA enhancer and promoter activity is low (Pang et al., 1997).
1.3 Deficiencies in the Prior Art
A major obstacle to contemporary cancer treatment using gene therapy is the problem of selectivity; that is, the ability to inhibit the multiplication of tumor cells, while leaving unaffected the function of normal cells. The therapeutic ratio (ratio of tumor cell killing to normal cell killing) of traditional tumor chemotherapy is only 1.5:1, clear evidence that more effective methods for the treatment and prophylaxis of prostatic hyperplasias and neoplasias are needed.
Thus, there remains a need for the development of improved expression vectors, and genetic constructs that can be used to effect high-level expression of selected therapeutic genes in a tissue-specific manner in the mammalian prostate. Also desirable are gene therapy vectors, and in particular viral and liposomal-mediated vectors for administering such therapeutic constructs to an animal in need thereof. The need also exists for effective treatment regimens for prostate cancer, and in particular, prostate tumors that circumvent the toxic side effects of existing therapies and provide more specific gene expression of the therapeutic constructs directly in the cells of the affected prostate. Tissue-specific enhancers and promoters that are active in prostate cells, and particularly in neoplastic or hyperplastic prostate cells, would represent a significant advance for those of skill in the oncologic arts, and would facilitate the creation of genetic expression constructs suitable for therapeutic ablation of prostate tissue, especially neoplastic prostate epithelium.